Purines such as adenosine have been shown to play a wide array of roles in biological systems. For example, physiological roles played by adenosine include, inter alia, modulator of vasodilation and hypotension, muscle relaxant, central depressant, inhibitor of platelet aggregation, regulator of energy supply/demand, responder to oxygen availability, neurotransmitter, and neuromodulator. (Bruns, Nucleosides & Nucleotides, 10(5), 931–934 (1991)). Because of its potent actions on many organs and systems, adenosine and its receptors have been the subject of considerable drug-development research (Daly, J. Med. Chem., 25, 197 (1982)). Potential therapeutic applications for agonists include, for instance, the prevention of reperfusion injury after cardiac ischemia or stroke, and treatment of hypertension and epilepsy (Jacobson, et al., J. Med. Chem., 35, 407–422 (1992)). Adenosine itself has recently been approved for the treatment of paroxysmal supra ventricular tachycardia (Pantely, et al., Circulation, 82, 1854 (1990)). Adenosine receptor agonists also find use as anti-arrhythmics, antinociceptives, anti-lipolytics, cerebroprotectives, and antipsychotics.
P2 receptors, are present in heart, skeletal, various smooth muscles, prostate, ovary, and brain and have been implicated in certain aggregation processes associated with thrombosis and as anti-hypertensive and anti-diabetic agents. Agonists that bind the P2 receptor induce activation of phospholipase C, which leads to the generation of inositol phosphates and diacyl glycerol with a subsequent rise in intracellular calcium concentration and muscle relaxation. P2 receptor antagonists block ADP-promoted aggregation in platelets and thereby exert an anti-thrombotic effect.
All P1 and P2 receptor nucleoside ligands suffer from chemical instability that is caused by the labile glycosidic linkage in the sugar moiety of the nucleoside. However, it has been found that relatively few ribose modifications are tolerated by the presently known agonists and antagonists of P1 and P2 receptors.
New compositions are needed that have improved chemical stability and that do not destroy the activity of such compounds.
The invention provides such compositions and methods of using them in the treatment of disease. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The following documents disclosed certain analogues containing adenine, thymidine, or uracil: Siddiqui et al., Nucleosides & Nucleotides, 15, 235–250 (1996); Katagiri et al., Tetr. Lett., 40, 9069–9072 (1999); Dyatkina et al., Bioorg. & Med. Chem., 6, 2639–2642 (1996); WO 95 08541 A (1995); WO 95 03304 A (1995); EP-A-0 577 558 (1994); U.S. Pat. No. 5,840,728 (1998); WO 98 05662 A (1998) U.S. Pat. No. 5,629,454 (1997); Laks et al., Tetr. Lett., 37, 2353–2356 (1996); Marquez et al., J. Med. Chem., 39, 3739–3747 (1996); Marquez et al., JACS, 120, 2780–2789 (1998); Ezzitouni et al., JCS, Perkin Trans., 1, 1073–1078 (1996); Marquez et al., Helv. Chim. Acta, 82, 2119–2129 (2000); Shin et al., JOC, 65, 2172–2178 (2000); H. R. Moon, JOC, 64, 4733–4741 (1999); A. Ezzitouni, JOC, 62, 4870–4873 (1997); Altmann et al., Tetr. Lett., 35, 2331–2334 (1994); Ezzitouni et al., JCS, Chem. Comm., 1345–1346 (1995); Theil et al., JCS, Perkin Trans., 1, 255–258 (1996); Rodriguez et al., Tetr. Lett., 34, 6233–6236 (1993); Marquez et al., Nucleosides & Nucleotides, 16, 1431–1434 (1997); V. E. Marquez, Nucleosides & Nucleotides, 18, 521–530 (1999); Jeong et al., Nucleosides & Nucleotides, 16, 1059–1062 (1997); Altmann et al. Tetr. Lett., 35, 7625–7628 (1994); Rodriguez et al., J. Med. Chem., 37, 3389–3399 (1994); U.S. Pat. No. 4,954,504 (1990); U.S. Pat. No. 5,063,233 (1991); Jacobson et al., J. Med. Chem., 35, 407–422 (1992).